stop-hae: a phase 3 study of adx-324 in hae

Conditions: Hereditary Angioedema

Summary: evaluate the efficacy safety, pharmacokinetics (pk), pharmacodynamics (pd), and health-related quality of life (hrqol) measures in participants with type i and type ii hae.

this phase 3 study will evaluate the efficacy of 2 dose levels and regimens of adx-324 in preventing hae attacks compared with placebo in participants with type i and type ii hae. the study will also evaluate safety, pharmacokinetics (pk), pharmacodynamics (pd), and health-related quality of life (hrqol) measures.

Eligibility criteria:
inclusion criteria: 1. age ≥18 years at the time of signing informed consent. 2. provided written informed consent and any authorizations required by local law and be willing to comply with all study requirements for the duration of the study. 3. have a documented diagnosis of hae-1/hae-2 (type i or ii) based upon all of the following (a, b, and c): a. documented clinical history consistent with hae (sc or mucosal, non-pruritic swelling episodes without accompanying urticaria). b. diagnostic testing (historical documentation or during screening, with option of one repeat test) that confirms 2 of the following: - c1-inh antigen level \<50% the lower limit of normal (lln). - c1-inh functional level \<50% lln. - c1-inh function ≥50% but ≤60% and a pathogenic mutation in the serping1 gene. - complement factor c4 level below the lln. c. have at least one of the following: - age ≤30 years at reported hae onset. - a family history consistent with hae-1/hae-2. - complement component 1q within the normal range. 4. experienced ≥1 investigator-confirmed hae attack in the first 4 weeks of screening or ≥2 investigator-confirmed hae attacks in 8 weeks of screening. 5. have access to, and the ability to use, at least one acute hae therapy to treat hae attacks (eg, plasma-derived or recombinant c1-inh concentrate or a bk2-receptor antagonist) that has previously been shown to be effective for the participant. 6. participants must be deemed medically appropriate for on-demand treatment as the sole medicinal management for their hae during the study, per investigator. 7. women of childbearing potential must have a negative serum pregnancy test during screening and a negative urine pregnancy test on study day 1 before study drugadministration and must agree to use acceptable contraceptive methods if engaged in sexual activity of childbearing potential (refer to section 13.2.2) from the time of signing the informed consent form (icf) until the eos visit or 1 month after study drug administration, whichever is longer. exclusion criteria: 1. concurrent diagnosis of another form of recurrent angioedema. examples include, but are not limited to, acquired angioedema, hae with normal c1-inh (previously known as hae type iii), idiopathic angioedema, and recurrent angioedema associated with urticaria. 2. any clinically significant medical history including, but not limited to, uncontrolled hypertension (defined as systolic blood pressure ≥160 mmhg or diastolic blood pressure ≥ 100 mmhg despite therapy), uncontrolled diabetes mellitus (hba1c \>9.0%), or current cardiovascular disease, including recent acute coronary syndrome (within the past 6 months), congestive heart failure (nyha class iii or iv), and significant arrhythmias. 3. history of alcohol or drug abuse within the previous year prior to screening, or current evidence of substance dependence or abuse and/or self-reported alcoholic intake averaging \>3 drinks/day. 4. any clinically significant renal disease, including chronic kidney disease (ckd) stage 3 or higher (egfr \< 60 ml/min/1.73 m²) or a history of nephrotic syndrome. 5. any clinically significant hepatic disease, such as active hepatitis, cirrhosis, steatosis, or hepatic insufficiency (child-pugh class b or c); screening alanine aminotransferase (alt) or aspartate aminotransferase (ast) \>2.5 × upper limit of normal (uln); or screening bilirubin direct \>1.5 × uln (unless due to gilbert's syndrome). one retest is permitted. 6. a history of coagulopathies or bleeding diathesis. 7. malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. 8. active infection (viral, bacterial, fungal, or parasitic) requiring systemic antimicrobial therapy that will not be completed at least 5 days before study day 1, or active infection not requiring antimicrobial therapy that is moderate or severe (eg, cold, flu, or covid-19) that has not resolved prior to study day 1. 9. known hiv infection (per participant history and/or medical records) or positive serology test for hepatitis b surface antigen (hbsag) or hepatitis c virus (hcv) during screening. 10. major surgery or significant traumatic injury within 30 days prior to signing the icf. 11. exposure to any of the following ltp for hae: a. chronic prophylaxis with c1-inh (cinryze, haegarda, ruconest) within 2 weeks prior to screening. b. chronic prophylaxis with berotralstat (orladeyo) within 3 weeks prior to screening. c. chronic prophylaxis with lanadelumab (takhzyro) within 8 weeks prior to the screening. d. androgen use within 12 weeks prior to screening. 12. exposure to any of the following medications: a. ace inhibitors within 4 weeks prior to screening. b. new use of or increase in dose of estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 3 months prior to screening. participants on a stable dose of estrogen-containing medications for ≥3 months prior to screening are eligible. 13. has a preplanned procedure during the study (screening through eos visit) for which use of short-term hae prophylaxis would be anticipated. 14. received treatment with another investigational product or device within 4 weeks or 5 half-lives, whichever is longer, prior to screening. 15. received prior treatment with any rna/dna-based therapy for hae (including adx-324) or is intolerant of any prior rna/dna-based therapy for any condition, excluding vaccines. 16. participant is breastfeeding. 17. any condition or abnormal laboratory value, ecg finding, vital sign, or physical examination finding that, in the investigator's opinion, would pose an unacceptable risk to the participant if they participate in the study. one repeat laboratory test and ecg is permitted without consultation with the sponsor. persistent abnormal findings of questionable clinical significance should be discussed with the sponsor.